The long term objective of this proposal is to develop a new and effective vaccine against influenza virus, using microspheres as an oral delivery system. The purpose of this Phase II study is to optimize the immunogenic potential of mucosally administered influenza virus vaccine incorporated into biodegradable and biocompatible microspheres and to evaluate the immunoprophylactic potential of such vaccines in mouse and squirrel monkey influenza infection models. The maximum and optimal amount of microsphere uptake and their distribution in the gastrointestinal and respiratory tracts will be determined by monitoring the fate of radiolabeled microspheres administered orally, intranasally, or systemically to BALB/c mice. The optimal dose of microencapsulated influenza virus for inducing a secretory immune response without oral tolerance will be determined by quantitating the influenza-specific antibodies in sera and secretions of mice after oral administration of various doses of antigen (microencapsulated versus free) followed by systemic challenge. The influence of preexisting secretory or circulatory antibodies on the immune response will be determined in mice primed by systemic or mucosal routes and mucosally boosted. The duration of immune responses induced by immunization with microencapsulated versus free antigen will be characterized by measuring antibody titers of one year. The ability of microspheres to prime animals for secondary immune responses with closely or less related influenza viruses will be tested in a mouse infection model. The efficacy of mucosal immunization with microencapsulated influenza virus will also be evaluated by measuring protection after challenge with live virus in squirrel monkeys. If Phase II studies are successfully accomplished, the assessment of efficacy after mucosal administration of microencapsulated influenza virus will be continued in Phase III in a human trial.